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PurposeThe purpose of this study was to evaluate RB1 expression and survival across ovarian carcinoma histotypes and how co-occurrence of BRCA1 or BRCA2 (BRCA) alterations and RB1 loss influences survival in tubo-ovarian high-grade serous carcinoma (HGSC).Experimental designRB1 protein expression was classified by immunohistochemistry in ovarian carcinomas of 7,436 patients from the Ovarian Tumor Tissue Analysis consortium. We examined RB1 expression and germline BRCA status in a subset of 1,134 HGSC, and related genotype to overall survival (OS), tumor-infiltrating CD8+ lymphocytes, and transcriptomic subtypes. Using CRISPR-Cas9, we deleted RB1 in HGSC cells with and without BRCA1 alterations to model co-loss with treatment response. We performed whole-genome and transcriptome data analyses on 126 patients with primary HGSC to characterize tumors with concurrent BRCA deficiency and RB1 loss.ResultsRB1 loss was associated with longer OS in HGSC but with poorer prognosis in endometrioid ovarian carcinoma. Patients with HGSC harboring both RB1 loss and pathogenic germline BRCA variants had superior OS compared with patients with either alteration alone, and their median OS was three times longer than those without pathogenic BRCA variants and retained RB1 expression (9.3 vs. 3.1 years). Enhanced sensitivity to cisplatin and paclitaxel was seen in BRCA1-altered cells with RB1 knockout. Combined RB1 loss and BRCA deficiency correlated with transcriptional markers of enhanced IFN response, cell-cycle deregulation, and reduced epithelial-mesenchymal transition. CD8+ lymphocytes were most prevalent in BRCA-deficient HGSC with co-loss of RB1.ConclusionsCo-occurrence of RB1 loss and BRCA deficiency was associated with exceptionally long survival in patients with HGSC, potentially due to better treatment response and immune stimulation.

Objectives The objective of this study was to evaluate SOX17, a transcription factor from the Sry high-mobility group–related box superfamily, as a diagnostic marker to determine site of origin using both whole-tissue sections and tissue microarrays (TMAs). Methods SOX17 immunohistochemistry was performed on gynecologic and nongynecologic tissues (N = 1004) using whole-tissue sections and both internally constructed and commercially available TMAs. SOX17 nuclear reactivity was scored as positive or negative on the whole-tissue sections and using the semiquantitative H score method on TMAs. Results Using both whole-tissue sections and TMAs, SOX17 was positive in 94% (n = 155) of endometrial tumors and 96% (n = 242) of ovarian tumors. All breast cases (n = 241) and vulvar/cervical squamous cell carcinomas (n = 150) were negative. Among 1004 tumors from 20 sites, the only organs with positive tumors were ovary, uterus, and testis. Conclusions SOX17 is a sensitive and specific marker for gynecologic origin in the tissues tested and may be a valuable adjunct to PAX8 and other commonly used markers to confirm endometrial or ovarian origin. SOX17 expression is lower in mucinous tumors, endocervical adenocarcinoma, high-grade neuroendocrine tumors, and undifferentiated/dedifferentiated endometrial carcinoma. [ABSTRACT FROM AUTHOR]

Objectives Our aim was to explore the performance of TRPS1 as an immunohistochemical diagnostic marker; find the optimal conditions for its use in breast carcinomas, especially triple-negative breast cancers (TNBCs); and compare its results in carcinomas of a select few organ sites, with an emphasis on gynecologic tumors. Methods Tissue microarrays from breast carcinomas (n = 197), endometrial adenocarcinomas (n = 69), ovarian tumors (n = 250), vulvar squamous cell carcinomas (n = 97), pancreatic ductal adenocarcinomas (n = 20), and gastric adenocarcinomas (n = 12) were stained with TRPS1 using 2 different conditions (protocol 1: high pH; protocol 2: low pH). Breast carcinomas consisted of hormone receptor (HR)–positive/ERBB2 (formerly HER2 or HER2/neu)–negative (n = 53) samples, HR-positive/ERBB2-positive (n = 6) samples, and TNBCs (n = 138). Results Comparing TRPS1 results in breast carcinomas vs tumors from other organ sites, the sensitivity of TRPS1 was 91% and 87%, respectively, while the specificity was 66% and 74% for protocol 1 and 2, respectively. For TNBCs vs gynecologic tumors, the sensitivity of TRPS1 was 89% and 85%, respectively, while the specificity was 65% and 73%, respectively. Conclusions TRPS1 stains approximately 90% of breast carcinomas but also up to 71% of endometrial carcinomas, albeit with a weaker median expression. Our data show that although TRPS1 is a highly sensitive marker for TNBCs, it is not as highly specific as previously reported. [ABSTRACT FROM AUTHOR]

Objectives: SOX10 expression helps identify melanocytic lesions. Over time, novel uses have been identified, such as expression in triple-negative breast cancer (TNBC). We evaluated the usefulness of SOX10 in breast pathology-specifically, identification and subtyping of TNBC and distinction from gynecologic carcinomas, use as a myoepithelial marker, and in the distinction of usual ductal hyperplasia (UDH) from atypical ductal hyperplasia (ADH).Methods: Several breast and gynecologic carcinoma tissue microarrays containing a total of 492 cases were stained with SOX10. Whole sections of 34 ADH, 50 UDH, and 29 ductal carcinoma in situ (DCIS) samples were also stained with SOX10.Results: SOX10 expression was identified in 67% of consecutive TNBC cases. Expression was mostly seen in nonapocrine, androgen receptor (AR)-negative TNBCs. All gynecologic carcinomas (n = 157) were negative. All UDH cases showed mosaic SOX10 expression, while all ADH cases lacked expression. All estrogen receptor (ER)-positive DCIS (n = 19) specimens were negative for SOX10, while 2 of 10 ER-negative DCIS specimens were positive for SOX10. The latter 2 cases showed SOX10-positive invasive carcinomas.Conclusions: SOX10 identifies nonluminal AR-type TNBC and is useful in distinguishing TNBC from gynecologic carcinomas. SOX10 can distinguish UDH from ADH. SOX10 is not useful in distinguishing ADH from DCIS. [ABSTRACT FROM AUTHOR]

Polyguanine tracts (PolyGs) are short guanine homopolymer repeats that are prone to accumulating mutations when cells divide. This feature makes them especially suitable for cell lineage tracing, which has been exploited to detect and characterize precancerous and cancerous somatic evolution. PolyG genotyping, however, is challenging because of the inherent biochemical difficulties in amplifying and sequencing repetitive regions. To overcome this limitation, we developed PolyG-DS, a next-generation sequencing (NGS) method that combines the error-correction capabilities of duplex sequencing (DS) with enrichment of PolyG loci using CRISPR-Cas9-targeted genomic fragmentation. PolyG-DS markedly reduces technical artifacts by comparing the sequences derived from the complementary strands of each original DNA molecule. We demonstrate that PolyG-DS genotyping is accurate, reproducible, and highly sensitive, enabling the detection of low-frequency alleles (<0.01) in spike-in samples using a panel of only 19 PolyG markers. PolyG-DS replicated prior results based on PolyG fragment length analysis by capillary electrophoresis, and exhibited higher sensitivity for identifying clonal expansions in the nondysplastic colon of patients with ulcerative colitis. We illustrate the utility of this method for resolving the phylogenetic relationship among precancerous lesions in ulcerative colitis and for tracing the metastatic dissemination of ovarian cancer. PolyG-DS enables the study of tumor evolution without prior knowledge of tumor driver mutations and provides a tool to perform cost-effective and easily scalable ultra-accurate NGS-based PolyG genotyping for multiple applications in biology, genetics, and cancer research. [ABSTRACT FROM AUTHOR]

Beginning with the discovery of the BRCA-associated ovarian cancer susceptibility genes and subsequent detailed examination of risk-reducing salpingo-oophorectomy (RRSO) specimens, a new paradigm of ovarian carcinogenesis has unfolded with attention to the distal fallopian tube. The primary focus has been an early cancer or neoplasm in the fallopian tube which is seen in virtually all incidentally discovered high-grade serous cancers in asymptomatic women. This high-frequency of tubal involvement in early serous neoplasm (usually in the form of serous tubal intraepithelial carcinoma—STIC) has galvanized attention to this organ as a primary source of this disease. However, an enduring mystery has been the relatively low frequency of STIC in the fallopian tubes of women with advanced malignancy. This paradox, a high frequency of tubal involvement early on and a low frequency of involvement later in the disease process, has spurred interest in other potential sources, such as the ovarian surface epithelium or cortical inclusions and the secondary Mullerian system. However, because essentially all high-grade serous carcinomas are linked by TP53 mutations, and because fallopian tubes frequently contain early serous proliferations (ESPs) with these mutations, attention has turned to the possibility that the nonmalignant but TP53 mutated tubal epithelium could be responsible for an eventual malignancy. Recent data have shown evidence of a lineage continuity between ESPs and concurrent serous carcinomas prompting the concept of "precursor escape". This creates a second component of the paradigm by which cells from early precursors are shed from the tube and undergo subsequent malignant transformation, emerging suddenly as widespread intraperitoneal malignancy. This dualistic model thus provides a unique pathway by which the future outcome (wide spread high-grade serous carcinomas—HGSC) is ultimately explained by going back in time to an early serous proliferation. This paradigm also brings the peritoneal cavity into focus, raising new questions about the potential co-variables or exposures that might facilitate the occasional malignant transformation of an ESP in the peritoneal cavity or on the peritoneal surface. [ABSTRACT FROM AUTHOR]

Background: Parity and breastfeeding are associated with systemic changes in maternal inflammation and reduced risk of ovarian cancer, but little is known about their impact on the ovarian tumor immune microenvironment., Methods: We evaluated the associations of self-reported parity and history of breastfeeding with tumor-infiltrating T cells among 1,706 ovarian carcinoma cases with tumor tissue collected across four studies. The abundance of tumor-infiltrating T cells was measured by multiplex immunofluorescence in tumor tissue microarrays. Odds ratios (OR) and 95% confidence intervals (CIs) for the positivity of tumor immune cells were calculated using beta-binomial models and stratified by histotype., Results: Compared to ovarian tumors in nulliparous women, there was no association between parity and ovarian tumor T cell abundance among all histotypes combined, but suggestion of increased cytotoxic T cells and T cell exhaustion among parous women with clear cell tumors. When restricted to parous women, history of breastfeeding was associated with increased odds for all T cell types (i.e., total, cytotoxic, helper, regulatory, and exhausted T cells), with ORs ranging from 1.11-1.42. For every 6 months of breastfeeding, we observed increased odds of activated helper T cell infiltration (CD3+CD4+CD69+, OR:1.13, 95% CI: 0.99-1.29), with a similar association for high-grade serous tumors, but lower odds in clear cell tumors (OR:0.43, 95% CI:0.21-0.87)., Conclusions: History of breastfeeding may alter the ovarian tumor immune microenvironment by modulating the abundance of tumor-infiltrating T cells., Impact: While replication is required, history of breastfeeding may play a role in activation of the ovarian tumor immune response.

Objective: Uterine serous carcinoma (USC) is a rare diagnosis but associated with high mortality. There is limited data to guide adjuvant treatment decisions in early stage disease. The purpose of this study is to evaluate the impact of adjuvant therapy on recurrence-free survival (RFS) and overall survival (OS) in early stage USC., Methods: Patients with stage I and II USC treated at a single institution from 1/2006-12/2019 were identified. Demographic, clinicopathologic, treatment and outcome data were collected. Data were compared using descriptive statistics. Survival analyses were performed using Kaplan-Meier and Cox proportional hazard methods., Results: Ninety-four patients were identified. Median follow-up time was 33.5 months. The median age was 68 years (range 49-87), the majority of patients were white (n=78, 83.0%), and the median BMI was 30.7 (range 14.2-57.3). Minimally-invasive surgical staging was performed in 59.6% of cases (n=56). Most patients had stage IA disease (n=70, 74.5%). Most patients (n=79, 84.0%) received adjuvant therapy, and a majority of patients received a combination of systemic chemotherapy and radiation therapy (n=55, 58.5%), with the most common combination being chemotherapy plus vaginal brachytherapy (n=42, 44.7%). Most patients (n=77, 81.9%) remain without evidence of disease, while 17 patients (18.1%) have recurred. Patients receiving 6 cycles of adjuvant chemotherapy experienced improved OS (p=0.004) and improved RFS (p=0.02) compared to those receiving no adjuvant chemotherapy., Conclusion: Patients with early stage USC who received six cycles of adjuvant chemotherapy had significantly improved OS and RFS when compared to those patients who did not receive adjuvant chemotherapy., (© The Author(s) 2025. Published by Oxford University Press on behalf of the Johns Hopkins Bloomberg School of Public Health. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

The fundamental steps in high-grade serous ovarian cancer (HGSOC) initiation are unclear, thus providing critical barriers to the development of prevention or early detection strategies for this deadly disease. Increasing evidence demonstrates most HGSOC starts in the fallopian tube epithelium (FTE). Current models propose HGSOC initiates when FTE cells acquire increasing numbers of mutations allowing cells to evolve into serous tubal intraepithelial carcinoma (STIC) precursors and then to full blown cancer. Here we report that epigenetically altered mesenchymal stem cells (termed high risk MSC-hrMSCs) can be detected prior to the formation of ovarian cancer precursor lesions. These hrMSCs drive DNA damage in the form of DNA double strand breaks in FTE cells while also promoting the survival of FTE cells in the face of DNA damage. Indicating the hrMSC may actually drive cancer initiation, we find hrMSCs induce full malignant transformation of otherwise healthy, primary FTE resulting in metastatic cancer in vivo . Further supporting a role for hrMSCs in cancer initiation in humans, we demonstrate that hrMSCs are highly enriched in BRCA1/2 mutation carriers and increase with age. Combined these findings indicate that hrMSCs may incite ovarian cancer initiation. These findings have important implications for ovarian cancer detection and prevention.